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Cunningham D.,Royal Marsden Hospital | Lang I.,National Institute of Oncology | Marcuello E.,Hospital de Sant Pau de Barcelona | Lorusso V.,Italian National Cancer Institute | And 7 more authors.
The Lancet Oncology | Year: 2013

Background: Elderly patients are often under-represented in clinical trials of metastatic colorectal cancer. We aimed to assess the efficacy and safety of bevacizumab plus capecitabine compared with capecitabine alone in elderly patients with metastatic colorectal cancer. Methods: For this open-label, randomised phase 3 trial, patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were randomly assigned in a 1:1 ratio via an interactive voice-response system, stratified by performance status and geographical region. Treatment consisted of capecitabine (1000 mg/m2 orally twice a day on days 1-14) alone or with bevacizumab (7·5 mg/kg intravenously on day 1), given every 3 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Efficacy analyses were based on the intention-to-treat population. The primary endpoint was progression-free survival. The trial is registered with ClinicalTrials.gov, number NCT00484939. Findings: From July 9, 2007, to Dec 14, 2010, 280 patients with a median age of 76 years (range 70-87) were recruited from 40 sites across ten countries. Patients were randomly assigned to receive either bevacizumab plus capecitabine (n=140) or capecitabine only (n=140). Progression-free survival was significantly longer with bevacizumab and capecitabine than with capecitabine alone (median 9·1 months [95% CI 7·3-11·4] vs 5·1 months [4·2-6·3]; hazard ratio 0·53 [0·41-0·69]; p<0·0001). Treatment-related adverse events of grade 3 or worse occurred in 53 (40%) patients in the combination group and 30 (22%) in the capecitabine group, and treatment-related serious adverse events in 19 (14%) and 11 (8%) patients. The most common grade 3 or worse adverse events of special interest for bevacizumab or chemotherapy were hand-foot syndrome (21 [16%] vs nine [7%]), diarrhoea (nine [7%] vs nine [7%]), and venous thromboembolic events (11 [8%] vs six [4%]). Treatment-related deaths occurred in five patients in the combination group and four in the capecitabine group. The most common any-grade adverse event of special interest for bevacizumab was haemorrhage (34 [25%] vs nine [7%]). Interpretation: The combination of bevacizumab and capecitabine is an effective and well-tolerated regimen for elderly patients with metastatic colorectal cancer. Funding: F Hoffmann-La Roche. © 2013 Elsevier Ltd. Source

Ladanyi A.,National Institute of Oncology
Pigment Cell and Melanoma Research | Year: 2015

The tumor microenvironment is shaped by interactions between malignant cells and host cells representing an integral component of solid tumors. Host cells, including elements of the innate and adaptive immune system, can exert both positive and negative effects on the outcome of the disease. In melanoma, studies on the prognostic impact of the lymphoid infiltrate in general, and that of T cells, yielded controversial results. According to our studies and data in the literature, a high peritumoral density of activated T cells, increased amount of B lymphocytes and mature dendritic cells (DCs) predicted longer survival, while intense infiltration by plasmacytoid DCs or neutrophil granulocytes could be associated with poor prognosis. Besides its prognostic value, evaluation of the components of immune infiltrate could provide biomarkers for predicting the efficacy of the treatment and disease outcome in patients treated with immunotherapy or other, non-immune-based modalities as chemo-, radio-, or targeted therapy. © 2015 John Wiley & Sons A/S. Source

Suba Z.,National Institute of Oncology
Recent Patents on Anti-Cancer Drug Discovery | Year: 2013

Literary data suggest apparently ambiguous interaction between menopausal status and obesity-associated breast cancer risk based on the principle of the carcinogenic capacity of estrogen. Before menopause, breast cancer incidence is relatively low and adiposity is erroneously regarded as a protective factor against this tumor conferred by the obesity associated defective estrogen-synthesis. By contrast, in postmenopausal cases, obesity presents a strong risk factor for breast cancer being mistakenly attributed to the presumed excessive estrogen-production of their adipose-tissue mass. Obesity is associated with dysmetabolism and endangers the healthy equilibrium of sexual hormone-production and regular menstrual cycles in women, which are the prerequisites not only for reproductive capacity but also for somatic health. At the same time, literary data support that anovulatory infertility is a very strong risk for breast cancer in young women either with or without obesity. In the majority of premenopausal women, obesity associated insulin resistance is moderate and may be counteracted by their preserved circulatory estrogen level. Consequently, it is not obesity but rather the still sufficient estrogen-level, which may be protective against breast cancer in young adult females. In obese older women, never using hormone replacement therapy (HRT) the breast cancer risk is high, which is associated with their continuous estrogen loss and increasing insulin-resistance. By contrast, obese postmenopausal women using HRT, have a decreased risk for breast cancer as the protective effect of estrogen-substitution may counteract to their obesity associated systemic alterations. The revealed inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology and promotes primary prevention measures. New patents recommend various methods for the prevention and treatment of obesity-related systemic disorders and the associated breast cancer. © 2013 Bentham Science Publishers. Source

Nagy P.,National Institute of Oncology
Antioxidants and Redox Signaling | Year: 2013

Significance: Disulfides are important building blocks in the secondary and tertiary structures of proteins, serving as inter- and intra-subunit cross links. Disulfides are also the major products of thiol oxidation, a process that has primary roles in defense mechanisms against oxidative stress and in redox regulation of cell signaling. Although disulfides are relatively stable, their reduction, isomerisation, and interconversion as well as their production reactions are catalyzed by delicate enzyme machineries, providing a dynamic system in biology. Redox homeostasis, a thermodynamic parameter that determines which reactions can occur in cellular compartments, is also balanced by the thiol-disulfide pool. However, it is the kinetic properties of the reactions that best represent cell dynamics, because the partitioning of the possible reactions depends on kinetic parameters. Critical Issues: This review is focused on the kinetics and mechanisms of thiol-disulfide substitution and redox reactions. It summarizes the challenges and advances that are associated with kinetic investigations in small molecular and enzymatic systems from a rigorous chemical perspective using biological examples. The most important parameters that influence reaction rates are discussed in detail. Recent Advances and Future Directions: Kinetic studies of proteins are more challenging than small molecules, and quite often investigators are forced to sacrifice the rigor of the experimental approach to obtain the important kinetic and mechanistic information. However, recent technological advances allow a more comprehensive analysis of enzymatic systems via using the systematic kinetics apparatus that was developed for small molecule reactions, which is expected to provide further insight into the cell's machinery. © 2013 Mary Ann Liebert, Inc. Source

Nagy P.,National Institute of Oncology
Methods in Enzymology | Year: 2015

Hydrogen sulfide is now a well-appreciated master regulator in a diverse array of physiological processes. However, as a consequence of the rapid growth of the area, sulfide biology suffers from an increasing number of controversial observations and interpretations. A better understanding of the underlying molecular pathways of sulfide's actions is key to reconcile controversial issues, which calls for rigorous chemical/biochemical investigations. Protein sulfhydration and coordination/redox chemical interactions of sulfide with heme proteins are the two most extensively studied pathways in sulfide biochemistry. These pathways are important mediators of protein functions, generate bioactive sulfide metabolites, contribute to sulfide storage/trafficking and carry antioxidant functions. In addition, inorganic polysulfides, which are oxidative sulfide metabolites, are increasingly recognized as important players in sulfide biology. This chapter provides an overview of our mechanistic perspective on the reactions that govern (i) sulfide's bioavailability (including the delicate enzyme machineries that orchestrate sulfide production and consumption and the roles of the large sulfide-storing pools as biological buffers), (ii) biological significance and mechanisms of persulfide formation (including the reduction of disulfides, condensation with sulfenic acids, oxidation of thiols with polysulfides and radical-mediated pathways), (iii) coordination and redox chemical interactions of sulfide with heme proteins (including cytochrome c oxidase, hemoglobins, myoglobins and peroxidases), and (iv) the chemistry of polysulfides. © 2015 Elsevier Inc. All rights reserved. Source

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